Anti-emetic esters of cyproheptadine-3-carboxylic acid and structurally related compounds

ABSTRACT

Certain esters of cyproheptadine-3-carboxylic acid and its bioisosteres are peripherally selective dopamine antagonists useful in the treatment of emesis caused by stimulation of dopamine receptors of the chemoreceptor trigger zone, as well as emesis and nausea resulting from other causes including post operative emesis, chronic pediatric vomiting, radiotherapy and chemotherapy induced emesis, and nausea associated with migraine attacks and dysmenorrhea or arising idiopathically. 
     They are also useful in the treatment of gastrointestinal disorders, such as gastro-oesophageal reflux caused by stimulation of dopamine receptors in the stomach or other causes and dyspepsia arising from delayed gastric emptying, post prandial dyspepsia or dyspepsia of unknown etiology.

This is a division of application Ser. No. 368,257, filed Apr. 14, 1982,now U.S. Pat. No. 4,412,999.

BACKGROUND OF THE INVENTION

This invention is concerned with compounds of structural formula I:##STR1## wherein X is --CH═CH--, --CH₂ --CH₂ --, --CH₂ --O--, --O--CH₂--, --S--CH₂ --, --CH₂ --S--, --S-- or --O--, and R is a 5- or6-membered nitrogen heterocyclic ring optionally fused to a benzo group,which are antiemetic agents because of their peripheral dopamineantagonist activity.

Severe emesis, and gastro-oesophageal reflux and/or dyspepsia caused bystimulation of peripheral dopamine receptors, are responsive totreatment with dopamine antagonists such as antipsychotic agents.However, such treatment may be accompanied by rather pronouncedundesirable central nervous system effects. Furthermore, in thetreatment of parkinsonism with a dopaminergic agent, such asbromocriptine or 1-dopa, the severe emetic and other side effectsthereof cannot be treated successfully with a centrally active dopamineantagonist without also blocking the desired antiparkinsonian action.Thus, there was a need for a drug which would control side effects ofthat origin but would not have the undesirable central effects of knowndopamine antagonists nor interfere with the central dopamine agonistactivity of a dopaminergic agent. One such agent, domperidone, has beendescribed in British Pat. No. 1,542,514.

Now, with the present invention there is provided a group of novelcompounds which have been derived from powerful dopamine antagonists ina manner that limits or eliminates their ability to traverse andblood-drain barrier and are thereby peripherally selective dopamineantagonists and are useful for the treatment of emesis caused bystimulation of dopamine receptors of the chemoreceptor trigger zone, aswell as emesis and nausea resulting from other causes including postoperative emesis, chronic pediatric vomiting, radiotherapy andchemotherapy induced emesis and nausea associated with migraine attacksand dysmenorrhea or arising idiopathically.

They are also useful in the treatment of gastrointestinal disorders,such as gastro-oesophageal reflux caused by stimulation of dopaminereceptors in the stomach or other causes and dysepepsia arising fromdelayed gastric emptying, post prandial dyspepsia or dyspepsia ofunknown etiology.

There are also provided novel processes for the preparation of the novelcompounds; pharmaceutical formulations employing one of the novelcompounds as the active agent alone or in combination with a dopamineagonist; and a method of treating emesis, gastro-oesophageal refluxand/or dyspepsia by the administration of an effective dopamineantagonistic amount of a novel compound of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of this invention have structural formula I:##STR2## or a pharmaceutically acceptable salt thereof, wherein

    ______________________________________                                        X is    (1) --CH═CH--,                                                                            (2) --CH.sub.2 --CH.sub.2 --,                                 (3) --CH.sub.2 --O--,                                                                         (4) --O--CH.sub.2 --,                                         (5) --CH.sub.2 --S--,                                                                         (6) --S--CH.sub.2 --,                                         (7) --S--, or   (8) --O--;                                            ______________________________________                                    

R is ##STR3## R¹ is (1) C₁₋₃ alkyl, or (2) ##STR4## and R² is (1)hydrogen, (2) C₁₋₃ alkyl, or (3) fluoro.

In a preferred embodiment of the novel compounds of this invention X is--CH═CH--, --CH₂ --CH₂ --, or --S--; R is ##STR5## R¹ is --CH₃ ; and R²is hydrogen.

In an even more preferred embodiment X is --CH═CH--; R is ##STR6## R¹ is--CH₃ and R² is hydrogen.

The group of novel compounds wherein X is --CH═CH-- exist asdextrorotatory and levorotatory atropisomers and racemic mixturesthereof. Substantially all of the desired peripheral dopamine antagonistactivity is provided by the levorotatory enantiomers and accordingly,although the racemates are included within the scope of the novelperipherally active dopamine antagonist compounds of this invention, thelevorotatory enantiomers are a preferred embodiment thereof.

The pharmaceutically acceptable salts of the novel compounds of thisinvention are acid addition salts formed from a novel compound and anorganic or inorganic acid recognized by the art as providing apharmaceutically acceptable acid addition salt, such as hydrochloride,hydrobromide, dihydrogen phosphate, sulfate, citrate, pamoate, pyruvate,napsylate, isethionate, maleate, fumarate, or the like.

These salts are readily prepared by mixing solutions of equimolecularamounts of the free base compound and the desired acid in suitablesolvents such as water, alcohols, ether or chloroform, followed byrecovery of the product by collecting the precipitated salt orevaporation of the solvent.

The novel process of this invention is illustrated by the followingreaction scheme: ##STR7## wherein X, R, R¹, and R² have the meaningspreviously assigned and Y is halogen, selected from Cl, Br, or I. Itcomprises mixing the two reactants in an organic solvent which is inertto the conditions of the reaction, such as hexamethyl phosphoramide(HMPA), dimethyl sulfoxide (DMSO), dimethylformamide (DMF),1,1,3,3-tetramethylurea, or the like, in the presence of an acidacceptor such as a strong organic base, for example, triethylamine(TEA), N-methylpiperidine, pyridine or the like, an inorganic base suchas sodium carbonate, aqueous sodium hydroxide or the like, or a stronglybasic ion exchange resin such as Dowex-1(OH⁻), IRA-400(OH⁻), or thelike. The preferred solvents are HMPA and DMSO and the preferred acidacceptor is TEA. The condensation reaction is conveniently run atambient temperatures (15°-25° C.) although any temperature from about 5°C. to about 100° C. is reasonable. Depending partially on temperature,the reaction is substantially complete in about 6 to about 24 hours. Itis convenient to let it go overnight, or for about 16 to about 20 hours.

The enantiomers of the cyproheptadine ester derivatives are prepared inaccordance with the above described process from the enantiomers of thecyproheptadine-3-carboxylic acids or, if desired, the racemates of thedesired esters are resolved by known techniques such as throughpreferential crystallization of a diastereomeric salt such as thatformed with di-p-toluyl-d-tartaric acid, as exemplified by theresolution of the simple ethyl ester in Example 1, step B.

In view of their useful activities, the compounds of Formula (I) may beformulated into various pharmaceutical compositions for administrationpurposes. To prepare the pharmaceutical compositions of this invention,an effective dopamine antagonist amount of the particular compound, inbase or acid-addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable, preferably,for administration orally, rectally or by parenteral injection. Forexample, in preparing the compositions in oral dosage form, any of theusual pharmaceutical media may be employed, such as, water, glycols,oils and alcohols for oral liquid preparations such as suspensionssyrups, elixirs and solutions; or solid carriers such as starches,sugars, kaolin, lubricants, binders, and disintegrating agents forpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules are the most advantageous oraldosage unit form, for which solid pharmaceutical carriers are obviouslyemployed. For parenteral compositions, the carrier will usually comprisesterile water, at least in large part, though other ingredients, forexample, may be prepared in which the carrier comprises saline solution,glucose solution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared for which appropriate liquid carriersand suspending agents may be employed. Acid addition salts of (I), dueto their increased water solubility compared to the corresponding baseform, are obviously more suitable in the preparation of aqueouscompositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. By the term "dosage unit form"as used herein is meant physically discrete units suitable as unitarydosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. Examples of suchdosage unit forms are tablets (including scored or coated tablets),capsules, pills, powder packets, wafers, injectable solutions orsuspensions, teaspoonsful and tablespoonsful, and segregated multiplesthereof.

The compounds of Formula I are advantageously formulated in combinationwith a dopamine agonist such as used in the treatment of parkinsonism.

The amount of active ingredient of Formula I in a unit dosage may befrom 1 to 400 mg and preferably from 5 to 240 mg whether used alone orin combination with a dopamine agonist.

The novel method of treatment of this invention comprises theadministration of one of the novel compounds, prophylactically ortherapeutically to a patient in need of a peripherally selectivedopamine antagonist. The route of administration can be oral, rectal,intravenous, intramuscular, or subcutaneous. Doses of 0.1 to 20mg/kg/day and preferably of 0.5 to 10 mg/kg/day of active ingredient aregenerally adequate, and if preferred it can be administered in divideddoses given two to four times daily.

It is to be noted that the precise unit dosage form and dosage leveldepend upon the requirements of the individual being treated and,consequently, are left to the direction of the therapist.

In the previous description of the novel compounds it was pointed outthat the cyproheptadine derivatives (X═--CH═CH--) exist as enantiomersand that the dextrorotatory enantiomers are substantially devoid ofantiemetic activity. Nonetheless those dextrorotatory enantiomers formanother embodiment of this invention being useful as starting materialsfor the racemic products resulting from a racemization process. Theracemization process comprises heating a solution of the dextroenantiomer in an inert solvent such as toluene, xylene, chlorobenzene,or the like until optical activity disappears. Temperatures of 65° toabout 150° C. for about 10 to 30 hours may be employed, and refluxingtoluene for about 26 hours is preferred.

EXAMPLE 1 (-)-(2,5-Dioxo-1-Pyrrolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylateStep A Preparation of (±)-ethyl5-(1-methyl-4-piperidiylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate

Racemic5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylicacid (0.03 mole) and an equal molar amount of boron trifluoride etheratein 60 ml of absolute ethanol was refluxed overnight. The solution wasevaporated to dryness and the residue was partitioned between ether anda saturated aqueous solution of sodium bicarbonate. The ether wasseparated and dried over MgSO₄. The resulting ethyl ester, crystallizedfrom acetonitrile, had m.p. 102°-103° C.

Step B Resolution of (±)-ethyl5-(1-methyl-4-piperidylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate

To a solution of 5.00 g (0.0139 mole) of the racemate in 50 ml ofabsolute ethanol was added 5.38 g (0.0139 mole) ofdi-p-toluoyl-d-tartaric acid in 50 ml of ethanol. The homogeneoussolution was warmed and then allowed to cool. The crystallineprecipitate that formed on cooling was removed by filtration, washedwith cold ethanol, and dried at 65° to give 3.90 g of material,designated A. The clear ethanol filtrate and washings were combined anddesignated B.

The 3.90 g of A was recrystallized twice from absolute ethanol to give aproduct with constant rotation, [α]₅₈₉ ²⁵ -165°, [α]₅₇₈ ²⁵ -176°, [α]₅₄₆²⁵ -211°, [α]₄₃₆ ²⁵ -523°, (c=0.0074 g/ml pyridine). This material (3.46g) was dissolved in water and a solution of sodium carbonate was added.The resulting precipitate was extracted into ether, washed with water,and dried over magnesium sulfate. After filtering, the ether wasevaporated. The residue was triturated with acetonitrile, collected byfiltration and dried at 78° in vacuo to give 1.50 g of (-)-ethyl5-(1-methyl-4-piperidylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate,m.p. 94°-96°; [α]₅₈₉ ²⁵ -207°, [α]₅₇₈ ²⁵ -220°, [α]₅₄₆ ²⁵ -268°, [α]₄₃₆²⁵ -728°, (c=0.008895 g/ml CHCl₃).

The ethanol filtrate and washings, B, were allowed to stand at roomtemperature for six days during which time the supernatant liquid wasdecanted from a small amount of crystalline residue. This supernatantliquid was allowed to stand fourteen days at room temperature, afterwhich time it was decanted again. The ethanol was removed byevaporation. The residue was dissolved in water and treated with anexcess of a solution of sodium carbonate. The resulting precipitate wasextracted into ether, washed with water, and dried over magnesiumsulfate. After filtering, the ether was evaporated to give 2.03 g of(+)-ethyl5-(1-methyl-4-piperidylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate,m.p. 94°-95°. This material was 93% optically pure as determined by itsrotation; [α]₅₈₉ ²⁵ +178°, [α]₅₇₈ ²⁵ +189°; [α]₅₄₆ ²⁵ +230°, [α]₄₃₆ ²⁵+622° (c=0.00869 g/ml CHCl₃).

Step C Preparation of(-)-5-(1-methyl-4-piperidylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylicacid

A solution of 1.24 g of (-)-ethyl5-(1-methyl-4-piperidylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylateand 4.12 ml of 2N potassium hydroxide in 55 ml of methanol was stirredat room temperature for seven days. The methanol was removed byevaporation at 25°. The residue was dissolved in water and extractedwith 50 ml of ether. The clear, colorless aqueous phase was acidifiedwith glacial acetic acid. The white precipitate that formed was removedby filtration, and washed thoroughly with water. After drying at 100° invacuo, 1.08 g of(-)-5-(1-methyl-4-piperidylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylicacid was obtained, m.p. 300°-305°; [α]₅₈₉ ²⁵ -180°; [α]₅₇₈ ²⁵ -194°;[α]₅₄₆ ²⁵ -239°; [α]₄₃₆ ²⁵ -675°; (c=0.004968 g/ml 0.10 NHCl). R_(f) :0.70 (fluorescent silica gel, n-butanol/acetic acid/water (5:2:3).

Similarly, there was prepared 93% optically pure(+)-5-(1-methyl-4-piperidylidene)-5H-dibenzo-[a,d]cycloheptene-3-carboxylicacid, m.p. 302°-305°, [α]₅₈₉ ²⁵ +152°; [α]₅₇₈ ²⁵ +163°; [α]₅₄₆ ²⁵ +201°;[α]₄₃₆ ²⁵ +572°; (c=0.005611 g/ml 0.10 NHCl).

Step D Preparation of (-)-(2,5-Dioxo-1-Pyrrolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate

To a mixture of 2.00 g (0.00544 mole) of(-)-5-(1-methyl-4-piperidylidene-5H-dibenzo[a,d]-cyclohepten-5-ylidene)-3-carboxylicacid, 10 ml of dimethylsulfoxide and 0.55 g (0.00544 mole) oftriethylamine was added a solution of 1.05 g (0.00544 mole) ofsuccinimidomethyl bromide in 10 ml of dimethyl sulfoxide. The mixturewas stirred overnight at ambient temperature. The mixture was filteredto recover unreacted starting acid. The recovered acid, 0.55 g oftriethylamine, 1.05 g of succinimidomethyl bromide, and 12 ml ofhexamethylphosphoramide were mixed and heated on a steam bath for 5minutes. The homogeneous solution was allowed to stir at ambienttemperature overnight. The dimethyl sulfoxide filtrate obtained abovewas combined with the hexamethylphosphoramide solution and this mixturewas poured into 400 ml of water containing 50 ml of an aqueous,saturated sodium carbonate solution. The mixture was extracted withthree 100 ml portions of toluene, and the combined toluene extracts werewashed with water, dried over magnesium sulfate, filtered, and thesolvent was removed by evaporation. Recrystallization of the residuefrom acetonitrile afforded pure (-)-(2,5-dioxo-1-pyrrolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate,m.p. 186°-188° C.; [α]₅₈₉ ²⁵ -211°; [α]₅₇₈ ²⁵ -255°; [α]₅₄₆ ²⁵ -274°;[α]₄₃₆ ²⁵ -752°; (c=0.5141, CHCl₃).

Anal. Calcd. for C₂₇ H₂₆ N₂ O₄ : C, 73.29; H, 5.92; N, 6.33. Found: C,73.09; H, 5.96; N, 6.37.

Employing the procedure substantially as described in Example 1, Step D,the following were prepared from succinimidomethyl bromide and theappropriate carboxylic acid:

(±)-(2,5-Dioxo-1-Pyrrolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylatem.p. 162°-165° C.

(+)-(2,5-Dioxo-1-Pyrrolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylatem.p. 185°-187° C.

(2,5-Dioxo-1-pyrrolidinyl)methyl10,11-dihydro-5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate,m.p. 140°-142° C. and

(2,5-Dioxo-1-Pyrrolidinyl)methyl9-(1-methyl-4-piperidinylidene)-9H-thioxanthene-2-carboxylate, m.p.178°-180° C.

EXAMPLE 2 (±)-(3-Methyl-2,5-dioxo-1-imidazolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate

To a mixture of 1.0 g (0.00302 mole) of(±)-5-(1-methyl-4-piperidylidene)-5H-dibenzo[a,d]-cycloheptene-3-carboxylicacid, 0.31 g (0.0030 mole) of triethylamine and 4 ml ofhexamethylphosphoramide was added 0.456 g (0.0030 mol) of1H-1-chloromethyl-3-methyl-2,5-dioxo-2,3,4,5-tetrahydroimidazole. Themixture was stirred and heated in an oil bath at 100° C. for 18 hours.After cooling, 25 ml of water and 25 ml of a saturated solution ofsodium carbonate were added to the reaction. The mixture then wasextracted with ten 50 ml aliquots of ether. The combined ether extractswere washed with ten 75 ml portions of water, dried over magnesiumsulfate, filtered, and the solvent was removed on a rotary evaporator.The white crystalline residue was recrystallized from acetonitrile toafford (±)-(3-methyl-2,5-dioxo-1-imidazolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate,m.p. 192°-194°.

Anal. Calcd. for C₂₇ H₂₇ N₃ O₄ : C, 70.88; H, 5.95; N, 9.19. Found: C,70.60; H, 6.12; N, 9.20.

EXAMPLE 3 (-)-(3-Methyl-2,5-dioxo-1-imidazolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate

When the levorotatory enantiomer was substituted for the racemiccarboxylic acid in the procedure of Example 2, and the reaction mixturewas heated on the steam bath for 10 minutes and then was kept at roomtemperature for 18 hours there was obtained(-)-(3-methyl-2,5-dioxo-1-imidazolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate,m.p. 188°-189° C.; [α]₅₈₉ -207; [α]₅₇₈ -220°; [α]₅₄₆ -270°; [α]₄₃₆ -733°(CHCl₃).

Anal. Calcd. for C₂₇ H₂₇ N₃ O₄ : C, 70.88; H, 5.95; N, 9.19. Found: C,71.02; H, 6.05; N, 9.29.

EXAMPLE 4 (+)-(3-Methyl-2,5-dioxo-1-imidazolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]-cycloheptene-3-carboxylate

When the dextrorotatory enantiomer was substituted for the racemiccarboxylic acid in the procedure of Example 2, and the reaction mixturewas heated on the steam bath for 10 minutes and then was kept at roomtemperature for 24 hours, there was obtained(+)-(3-methyl-2,5-dioxo-1-imidazolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate,m.p. 189°-190°; [α]₅₈₉ ²⁵ +208°; [α]₅₇₈ ²⁵ +222°; [α]₅₄₆ ²⁵ +270°;[α]₄₃₆ ²⁵ +733° (CHCl₃).

Anal. Calcd. for C₂₇ H₂₇ N₃ O₄ : C, 70.88; H, 5.95; N, 9.19.

Found: C, 71.12; H, 6.10; N, 9.20.

EXAMPLE 5 Racemization of(+)-(3-methyl-2,5-dioxo-1-imidazolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate

A solution of 0.50 g of (+)-(3-methyl-2,5-dioxo-1-imidazolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate,[α]₅₈₉ ²⁵ =+208°, in 50 ml of toluene was stirred and refluxed for 26hours. At the end of this time, the solution showed [α]₅₈₉ ²⁵ =0.0°.Evaporation of the toluene in vacuo gave chromatographically pure(±)-(3-methyl-2,5-dioxo-1-imidazolidinyl)methyl5-(1-methyl-4-piperidinylidene)-5H-dibenzo[a,d]cycloheptene-3-carboxylate,m.p. 191°-194°.

EXAMPLE 6 (±)-((2,3-Dihydro-3-methyl-2-oxo-1H-Benzimidazol-1-yl)-methyl)5-(1-methyl-4-piperidinylidene)-5H-dibenzo-[a,d])cycloheptene-3-carboxylat

To a mixture of 1.00 g (0.00302 mol) of(±)-5-(1-methyl-4-piperidylidene)-5H-dibenzo[a,d]-cycloheptene-3-carboxylicacid, 0.31 g (0.0030 mol) of triethylamine, and 8 ml ofhexamethylphosphoramide (HMPA) was added 0.60 g (0.0031 mol) of1-chloromethyl-1,2-dihydro-3-methyl-3H-benzimidazol-2-one. The mixturewas stirred and heated in an oil bath at 100° C. for 10 hours. Aftercooling, 50 ml of a saturated solution of sodium carbonate and 200 ml ofwater was added to the reaction. The mixture was extracted with four 75ml aliquots of toluene. The combined toluene extracts were washed withfive 100 ml portions of water, dried over magnesium sulfate, filtered,and the toluene was removed on a rotary evaporator. The whitecrystalline residue was recrystallized from acetonitrile to afford 0.64g (43%) of(±)-((2,3-dihydro-3-methyl-2-oxo-1H-benzimidazol-1-yl)-methyl)5-(1-methyl-4-piperidinylidene)-5H-dibenzo-[a,d])cycloheptene-3-carboxylate,m.p. 182°-184° C.

Anal. Calcd. for C₃₁ H₂₉ N₃ O₃ : C, 75.74; H, 5.95; N, 8.55. Found: C,75.75; H, 6.01; N, 8.66.

EXAMPLE 7 (±)-(1H-Imidazol-1-yl)methyl5-(1-methyl-4-piperidylidene)-5H-dibenzo[a,d]-cycloheptene-3-carboxylate

Employing the procedure substantially as described in Example 3 butsubstituting for the1-chloromethyl-1,3-dihydro-3-methyl-3H-benzimidazole-2-one used therein,an equimolecular amount of (1H-imidazol-1-yl)methyl bromide, the racemicsubject compound was prepared, in comparable yield, m.p. 118°-121° C.

Anal. Calcd. for C₂₆ H₂₅ N₃ O₂ : C, 75.89; H, 6.12; N, 10.21. Found: C,75.51; H, 6.17; N, 10.18.

Following the procedures substantially as described in Examples 1through 7, the following compounds are prepared from the appropriatecarboxylic acid and RCH₂ Br in the presence of TEA.

    ______________________________________                                         ##STR8##                                                                                                      optical                                      R             R.sup.1    R.sup.2 activity                                     ______________________________________                                         ##STR9##     CH.sub.3 CH.sub.3 CH.sub.2 C.sub.3 H.sub.5 CH.sub.2 C.sub.3                   H.sub.5 CH.sub.2 C.sub.3 H.sub.5                                                         7-CH.sub.3 7-F H 7-CH.sub.3 7-F                                                       (±), (+), (-) (±), (+), (-)                                             (±), (+), (-) (±), (+), (-)                                             (±), (+), (-)                              ##STR10##    CH.sub.3 CH.sub.3 CH.sub.2 C.sub.3 H.sub.5 CH.sub. 2                          C.sub.3 H.sub.5 CH.sub.2 C.sub.3 H.sub.5                                                 7-CH.sub.3 7-F H 7-CH.sub.3 7-F                                                       (±), (+), (-) (±), (+), (-)                                             (±), (+), (-) (±), (+), (-)                                             (±), (+), (-)                              ##STR11##    CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 C.sub.3 H.sub.5                           CH.sub.2 C.sub.3 H.sub.5 CH.sub.2 C.sub.3 H.sub.5                                        H 7-CH.sub.3 7-F H 7-CH.sub.3 7-F                                                     (+), (-) (±), (+), (-) (±), (+),                                        (-) (±), (+), (-) (±), (+), (-)                                         (±), (+), (-)                              ##STR12##    CH.sub.3 CH.sub. 3 CH.sub.3 CH.sub.3 CH.sub.2 C.sub.3                         H.sub.5 CH.sub.2 C.sub.3 H.sub.5 CH.sub.2 C.sub.3 H.sub.5                                H H 7-CH.sub.3 7-F H 7-CH.sub.3 7-F                                                   (-) (+) (±), (+), (-) (±), (+),                                         (-) (±), (+), (-) (±), (+), (-)                                         (±), (+), (-)                             ______________________________________                                         ##STR13##                                                                    X = CH.sub.2 CH.sub.2, CH.sub.2O, OCH.sub.2, CH.sub.2S,                       SCH.sub.2, Sor O                                                              R               R.sup.1     R.sup.2                                           ______________________________________                                         ##STR14##      CH.sub.3 CH.sub.3 CH.sub.2 C.sub.3 H.sub.5 CH.sub.2                           C.sub.3 H.sub.5 CH.sub.2 C.sub.3 H.sub.5                                                  7-CH.sub.3 7-F H 7-CH.sub.3 7-F                    ##STR15##      CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 C.sub.3 H.sub.5                           CH.sub.2 C.sub.3 H.sub.5 CH.sub.2 C.sub.3 H.sub.5                                         H 7-CH.sub.3 7-F H 7-CH.sub.3 7-F                  ##STR16##      CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 C.sub.3 H.sub.5                           CH.sub.2 C.sub.3 H.sub.5 CH.sub.2 C.sub.3 H.sub.5                                         H 7-CH.sub.3 7-F H 7-CH.sub.3 7-F                  ##STR17##      CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.2 C.sub.3 H.sub.5                           CH.sub.2 C.sub.3 H.sub.5 CH.sub.2 C.sub.3 H.sub.5                                         H 7-CH.sub.3 7-F H 7-CH.sub.3 7-F                 ______________________________________                                    

What is claimed is:
 1. A compound of structural formula: ##STR18## or apharmaceutically acceptable salt thereof, wherein X is

    ______________________________________                                        (1) CH.sub.2O,      (2) OCH.sub.2,                                            (3) CH.sub.2S,      (4) SCH.sub.2,                                            (5) S, or           (6) O;                                                    ______________________________________                                    

R is ##STR19## R¹ is (1) C₁₋₃ alkyl, or (2) ##STR20## and R² is (1)hydrogen, (2) C₁₋₃ alkyl, or (3) fluoro.
 2. The compound of claim 1wherein X is --S--; R is ##STR21##R¹ is --CH₃ and R² is hydrogen.
 3. Apharmaceutical peripherally selective dopamine antagonist compositioncomprising a pharmaceutical carrier and an effective peripherallyselective dopamine antagonist amount of a compound of structuralformula: ##STR22## or a pharmaceutically acceptable salt thereof,wherein X is

    ______________________________________                                        (1) CH.sub.2O,      (2) OCH.sub.2,                                            (3) CH.sub.2S,      (4) SCH.sub.2,                                            (5) S, or           (6) O;                                                    ______________________________________                                    

R is ##STR23## R¹ is (1) C₁₋₃ alkyl, or (2) ##STR24## and R² is (1)hydrogen, (2) C₁₋₃ alkyl, or (3) fluoro.
 4. The composition of claim 3comprising the compound wherein X is --S--;R is ##STR25## R¹ is --CH₃and R² is hydrogen.
 5. A pharmaceutical centrally selective dopamineagonists composition comprising a pharmaceutical carrier, a dopamineagonist and an effective peripherally selective dopamine antagonistamount of a compound of structural formula: ##STR26## or apharmaceutically acceptable salt thereof, wherein X is

    ______________________________________                                        (1) CH.sub.2O,      (2) OCH.sub.2,                                            (3) CH.sub.2S,      (4) SCH.sub.2,                                            (5) S, or           (6) O;                                                    ______________________________________                                    

R is ##STR27## R¹ is (1) C₁₋₃ alkyl, or (2) ##STR28## and R² is (1)hydrogen, (2) C₁₋₃ alkyl, or (3) fluoro.
 6. The composition of claim 5comprising the compound wherein X is --S--;R is ##STR29## R¹ is --CH₃and R² is hydrogen.
 7. A method of treating emesis, gastro-oesophagealreflux and/or dyspepsia comprising the prophylactic or therapeuticadministration to a patient in need of such treatment of an effectivedopamine antagonist amount of a compound of structural formula:##STR30## or a pharmaceutically acceptable salt thereof, wherein X is

    ______________________________________                                        (1) CH.sub.2O,      (2) OCH.sub.2,                                            (3) CH.sub.2S,      (4) SCH.sub.2,                                            (5) S, or           (6) O;                                                    ______________________________________                                    

R is ##STR31## R¹ is (1) C₁₋₃ alkyl, or (2) ##STR32## and R² is (1)hydrogen, (2) C₁₋₃ alkyl, or (3) fluoro.
 8. The method of claim 7wherein X is --S--;R is ##STR33## R¹ is --CH₃ and R² is hydrogen.